Autoimmune disease Flashcards
1
Q
Give 2 examples of organ-specific autoimmune disease
A
- Graves - TSH receptors in thyroid
- Type 1 diabetes - beta cells of pancreas
2
Q
Give examples of HLA B27-associated spondyloarthropathies
A
- Ankylosing spondylitis, undifferentiated spondyloarthropathu, reactive arthritis, psoriatic arthritis, urethritis, iritis
- Spectrum of severity and HLA B27 associated
- Associated with bowel inflamamtion
3
Q
What is autoimmunity?
A
- The immune system has various regulatory controls to prevent it from attacking self-proteins and cells.
- Failure of these controls will result in immune attack of host components – known as autoimmunity.
4
Q
What is immune tolerance?
A
- Immune system doesnt attack self proteins or cells - it is tolerant to them
- Central tolerance - destroy self-reactive T or B cells before the enter the circulation
- Peripheral tolerance - destroy or control any self-reactive T or B cells which dont enter the circulation
5
Q
How does central tolerance deal with B cells?
A
- If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
6
Q
How does the thymus choose which T cells to keep?
A
- Doesn’t bind to any self-MHC at all = death by neglect (apoptosis)
- Binds self-MHC too strongly = negative selection - apoptosis
- Binds self-MHC weakly = positive selection, signal to survive
7
Q
What is AIRE?
A
- Autoimmune regulator
- promotes self-tolerance by allowing thymic expression of genes from other tissues
- Mutations in AIRE result in multi-organ autoimmunity
- Allows all of the proteins to be presented in the thymus, to allow selection, but problem with it causes rampant autoimmunity
- Autoimmune polyendocrinopathy syndrome type 1 -> hyperPT, hyperT, adrenal failure etc
8
Q
What happens if autoreactive T cells survive central tolerance control?
A
Peripheral tolerance
- Ignorance
- Anergy
- Regulation
9
Q
What is ignorance?
A
- if antigen is present in too low a conc to reach the threshold for T cell receptor triggering (immunologically privileged site eg brain, eye)
10
Q
What is anergy?
A
- Naive T cells need costimulatory signals in order to become activated - MHC-T-cell interaction, co-stimulatory signal and cytokine signal
- Most cells lack costim proteins and MHC class II
- If a naive T cell sees its MHC/peptide ligand without appropriate costimulatory protein, it becomes anergic
- So if APC doesnt present B7 for CD28 receptor, it wont proliferate and so will become anergic
11
Q
What is regulation?
A
- Treg cells can inhibit other T cells
- can stop T cell response by using inhibitory signals (IL-10 and TGF-beta) on nearby T cells
- FOXP3 is a TF of Treg cells to help regulate T cells
- Defective Treg can cause autoimmunity
- CD4+ and CD25+
12
Q
What happens if there is a mutation in FOXP3?
A
- Can lead to severe and fatal autoimmune disorder - IPEX syndrome
13
Q
How are there different types of MHC?
A
- Each copy of chr6 carries 3 different MHC class I (a,b,c) and 3 different MHC class II genes (DR,DP,DQ)
- High levels of genetic variation (polymorphism)
14
Q
What gender differences are there in autoimmune disease?
A
- SLE and MS are 10 times more common in females
- Diabetes is equal
- Ankylosing spondylitis is 3x more common in males
15
Q
What environmental factors may affect it?
A
- Hygiene hypothesis
- Smoking and RA
16
Q
What might trigger a breakdown of self-tolerance?
A
- Loss of/ problem with reg cells
- Release of sequestered Ag
- Modification of self
- Molecular mimicry
17
Q
Modification of self - what is citrullination?
A
- Citrullin is an AA, not coded for by DNA
- Arginine can be converted to citrulline as post translational modification by PAD enzymes
- citrullination may be increased by inflammation
- Autoantibodies to citrullinated proteins are seen in RA
- Now used for diagnosis
18
Q
How does molecular mimicry cause rheumatic fever?
A
- Disease is triggered by infection of streptococcus pyogenes
- Abs to strep cell wall Ags may cross-react with cardiac muscle
- Plasma cell produces Abs, binds to bacteria and clears disease
- Same Ab cross-reacts with heart tissue -> rheumatic fever
19
Q
What causes graves?
A
- Autoantibodies bind to TSH receptor and stimulate it -> hyperT
- Disease can be transferred from mother to foetus with IgG Abs
20
Q
What causes Myasthenia gravis?
A
- Autoantibodies bind to Ach receptor and block Ach binding
- Also leads to receptor internalisation and degradation
- Causes muscle weakness, as no Na influx, so no muscle contraction
21
Q
What causes SLE?
A
- Autoantibodies to soluble antigens form immune complexes
- Deposited in tissue, e.g. blood vessels, joints, renal glomeruls
- Can lead to activation of complement and phagocytic cells
- Immune complexes depositing in kidney can lead to renal failure
22
Q
What happens if IgG mediated autoimmune antibodies cross the placenta?
A
- Patient with graves makes anti-TSHR Abs
- Transfer of Abs cross the placenta into the foetus
- Newborn infant also suffers from grave
- plasmaphoresis removes maternal anti-TSHR Abs and cure the disease
23
Q
How do T-cells cause autoimmune disease?
A
- Direct killing by CD8+ CTL
- Self-destruction induced by cytokines such as TNFa
- Recruitment and activation of macrophages lead to bystander tissue destruction
- MS
- Insulin-dependent DM
24
Q
What are Th17 cells?
A
- T helper cells that produce IL-17
- They are implicated in autoimmune diseases such as spondyloarthropathy, MS and diabetes
- Highly inflammatory
- Produce cytokines involved in recruitment, migration and activation of immune cells -> more and more damage
25
Q
What therapeutic strategies do we have against autoimmune diseases?
A
- NSAIDs and corticostroids to dampen down inflammation
- T and B cell depletion (anti-TNF, anti-VLA4 (blocks adhesion))
- Antigen specific therapies in development
